Abstract: Tumors of the central nervous system (CNS) comprise nearly one quarter of all childhood cancers. Although progress has been made in the treatment of some types of childhood cancer, the outcome for children with primary CNS tumors has remained bleak and little advancement has been made in the last decade. In addition, due to the adverse effects of the tumor on brain development or the treatment required to control its growth, survivors of childhood brain tumors often have severe neurodevelopmental defects that negatively impact their quality of life. Thus, there is a need for better treatments specific for childhood brain tumors. Current models suggest that only a few atypical cells within the cancerous mass are responsible for the initiation, growth and recurrence of brain tumors. These transformed cells have both the defining properties of neural stem cells and the ability to initiate cancer - thus, these cells are referred to as 'brain tumor stem (BTS) cells'. While the isolation of neural stem cells is fairly well established, the isolation of BTS cells remains a difficult and complex issue, suggesting the need for innovative approaches to isolate and characterize these cells. The development of induced pluripotent stem cells (somatic cells that have been reprogrammed to an embryonic-like pluripotent state by retroviral-mediated introduction of specific transcription factors) represents a powerful new approach that might alleviate such confounding issues. Thus, the goals of the proposed project are: 1) to reprogram brain tumor cells towards a more stem-like phenotype;2) to characterize the tumorigenic potential of such reprogrammed tumor stem-like cell lines;and 3) to identify chemical compounds that specifically target the reprogrammed tumor stem-like cells. Completion of these studies will provide a directed strategy for novel therapeutics to specifically target the cellular population responsible for the initiation, growth and recurrence of pediatric brain tumors. Public Health Relevance: Brain tumors are the second leading cause of cancer-related death in children in the United States and medulloblastoma is the most common pediatric brain tumor. An increasing amount of evidence suggests that only a few atypical cells (brain tumor stem cells) within the cancerous mass are responsible for the initiation, growth and recurrence of primary brain tumors. Brain tumor stem cells appear to be resistant to traditional chemo- and radiation therapies compared with the more differentiated cells in the cancerous mass, suggesting a mechanism underlying tumor recurrence after treatment. Thus, the focus of the present grant proposal is to generate stable brain tumor stem cell lines and to identify chemical compounds that specifically target the reprogrammed tumor stem-like cells